Neuroinflammation during stroke and Gaucher’s disease : How monocyte-derived macrophages and microglia shape the inflammatory environment of the brain
Författare
Summary, in English
The human brain is a complex and finely tuned organ, constantly monitored and maintained by its resident immune cells.
Among these, microglia are the primary regulators of the brain immune environment under physiological conditions, and monocyte-derived macrophages contribute mainly to pathological states such as ischemic stroke and neuronopathic Gaucher’s disease (GD). These two diseases, although different in origin, one acute and vascular, the other chronic and genetic, share a common feature: a disruption in immune homeostasis marked by neuroinflammation.
Using flow cytometry, gene expression profiling, and induced pluripotent stem cell (iPSC)-derived cell modeling, this work demonstrated that monocytes and microglia are dynamically regulated by intrinsic factors and extrinsic stimuli. During human aging, circulating monocyte subsets undergo sex-dependent transcriptional remodeling, with females exhibiting stronger anti-inflammatory aging signatures. This was particularly evident in the upregulation of ANXA1 in female non-classical monocytes. Additionally, age-associated increases in the scavenger receptor CD36 were observed across all monocyte subtypes.
In ischemic stroke patients, monocyte frequency and gene expression patterns predict recovery, particularly through the expansion of intermediate monocytes and the downregulation of inflammatory mediators. A panel of recovery-associated markers: CD91, CD36, TGM2, SLC24A4, and CD38, were identified, with CD36 in intermediate monocytes emerging as a novel marker of recovery.
In neuronopathic GD, human iPSC-derived microglia (hiMG) exhibit intrinsic impairments in cytokine signaling and lysosomal function under immune stimulation, indicating chronic neuroimmune dysfunction. These changes suggest a brain-specific immune phenotype distinct from peripheral macrophages and support a role for microglia in GD-associated neurodegeneration.
In summary, this thesis explores how peripheral monocytes and brain-resident microglia, both part of the mononuclear phagocyte system, shape the neuroinflammatory processes during aging, ischemic stroke, and GD. It highlights how immune responses are influenced by age, sex, and disease state, providing mechanistic insight and models for developing future immune-targeted therapies for neurological diseases.
Among these, microglia are the primary regulators of the brain immune environment under physiological conditions, and monocyte-derived macrophages contribute mainly to pathological states such as ischemic stroke and neuronopathic Gaucher’s disease (GD). These two diseases, although different in origin, one acute and vascular, the other chronic and genetic, share a common feature: a disruption in immune homeostasis marked by neuroinflammation.
Using flow cytometry, gene expression profiling, and induced pluripotent stem cell (iPSC)-derived cell modeling, this work demonstrated that monocytes and microglia are dynamically regulated by intrinsic factors and extrinsic stimuli. During human aging, circulating monocyte subsets undergo sex-dependent transcriptional remodeling, with females exhibiting stronger anti-inflammatory aging signatures. This was particularly evident in the upregulation of ANXA1 in female non-classical monocytes. Additionally, age-associated increases in the scavenger receptor CD36 were observed across all monocyte subtypes.
In ischemic stroke patients, monocyte frequency and gene expression patterns predict recovery, particularly through the expansion of intermediate monocytes and the downregulation of inflammatory mediators. A panel of recovery-associated markers: CD91, CD36, TGM2, SLC24A4, and CD38, were identified, with CD36 in intermediate monocytes emerging as a novel marker of recovery.
In neuronopathic GD, human iPSC-derived microglia (hiMG) exhibit intrinsic impairments in cytokine signaling and lysosomal function under immune stimulation, indicating chronic neuroimmune dysfunction. These changes suggest a brain-specific immune phenotype distinct from peripheral macrophages and support a role for microglia in GD-associated neurodegeneration.
In summary, this thesis explores how peripheral monocytes and brain-resident microglia, both part of the mononuclear phagocyte system, shape the neuroinflammatory processes during aging, ischemic stroke, and GD. It highlights how immune responses are influenced by age, sex, and disease state, providing mechanistic insight and models for developing future immune-targeted therapies for neurological diseases.
Avdelning/ar
Publiceringsår
2025
Språk
Engelska
Publikation/Tidskrift/Serie
Lund University, Faculty of Medicine Doctoral Dissertation Series
Avvikelse
2025:91
Fulltext
- Available as PDF - 17 MB
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Dokumenttyp
Doktorsavhandling
Förlag
Lund University, Faculty of Medicine
Ämne
- Neurosciences
Nyckelord
- Monocytes
- Stroke
- Gene expression
- Neuroinflammation
- Recovery
- iPSC-derived microglia
- Gaucher's disease
- Lysosomal dysfunction
- Disease modeling
Aktiv
Published
Projekt
- Characterisation of human monocytes for age and gender signatures and during stroke
Forskningsgrupp
- Stem Cells & Restorative Neurology
Handledare
- Zaal Kokaia
- Emanuela Monni
- Arne Lindgren
- Henrik Ahlenius
- Olle Lindvall
ISBN/ISSN/Övrigt
- ISSN: 1652-8220
- ISBN: 978-91-8021-744-6
Försvarsdatum
18 september 2025
Försvarstid
09:00
Försvarsplats
Segerfalksalen, BMC A10, Sölvegatan 17 i Lund
Opponent
- Kate Lykke Lambertsen (Associate Professor)